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Concept
CHEK2
Résumé
CHEK2 (Checkpoint kinase 2) is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.
The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1. Its location on chromosome 22 stretches from base pair 28,687,742 to base pair 28,741,904.
The CHEK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 amino acids and the following domains:
N-terminal SQ/TQ cluster domain (SCD)
Central forkhead-associated (FHA) domain
C-terminal serine/threonine kinase domain (KD)
The SCD domain contains multiple SQ/TQ motifs that serve as sites for phosphorylation in response to DNA damage. The most notable and frequently phosphorylated site being Thr68.
CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD phosphorylation causes CHK2 dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form the dimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates.
The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates cell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.
When DNA undergoes a double-strand break, CHK2 is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2. Once activated, CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). Thus, CHK2's inhibition of the CDC25 phosphatases prevents entry of the cell into mitosis. Furthermore, the CHK2 protein interacts with several other proteins including p53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1.
Source officielle
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